Seletalisib (UCB5857) (UCB5857) is a potent and specific PI3Kδ inhibitor (IC50: 12 nM).

PI3Kδ:12 nM

Seletalisib 能够在 B 细胞系中 BCR 激活后阻断 AKT 磷酸化。在用 Seletalisib 处理的 PBMCs 或其他细胞类型中没有观察到细胞性毒性迹象。Seletalisib 阻止活化 T 细胞产生多种细胞因子，并抑制 T 细胞向 Th1、Th2 和 Th17 亚型的分化。此外，Seletalisib 抑制 B 细胞的增殖和细胞因子释放。在人类全血测定中，Seletalisib 抑制 B 细胞激活时的 CD69 表达和抗 - IgE 介导的嗜碱细胞脱颗粒。

Seletalisib在大鼠中显著抑制TCR激活后的IL-2释放。在所有测试剂量中观察到抑制作用，剂量≥1 mg/kg时几乎完全抑制。Seletalisib具有强大的体内效果，估算的IC50值<10 nM。

Seletalisib is dissolved 1 mM solution in DMSO, and tested in a concentration-response, to explore the effects of PI3Kδ-specific inhibition compared with complete inhibition of class I PI3K signaling. In addition, seletalisib is tested in the BioMap BT cell system at concentrations of 1000, 100, 10, and 1 nM. An activity profile is generated based on the effect of the compounds on the levels of cellular readouts, including cytokines, growth factors, adhesion molecules, and proliferation endpoints.

Rats are dosed with Seletalisib (0.1-10 mg/kg in 500 μL volume) or vehicle via oral gavage 30 min prior to i.v. administration of anti- CD3 antibody administered in a 200 μL dose volume. The vehicle is methylcellulose or saline for oral and i.v. administration, respectively. Seletalisib levels and IL-2 levels are measured.